Adenosine A2a Receptor Antagonism Restores Additive Cytotoxicity by Cytotoxic T Cells in Metabolically Perturbed Tumors Article Swipe
Jeroen Slaats
,
Esther Wagena
,
Daan Smits
,
Annemarie A. Berends
,
Ella Peters
,
Gert‐Jan Bakker
,
Merijn van Erp
,
Bettina Weigelin
,
Gosse J. Adema
,
Peter Friedl
·
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1158/2326-6066.cir-22-0113
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1158/2326-6066.cir-22-0113
Cytotoxic T lymphocytes (CTL) are antigen-specific effector cells with the ability to eradicate cancer cells in a contact-dependent manner. Metabolic perturbation compromises the CTL effector response in tumor subregions, resulting in failed cancer cell elimination despite the infiltration of tumor-specific CTLs. Restoring the functionality of these tumor-infiltrating CTLs is key to improve immunotherapy. Extracellular adenosine is an immunosuppressive metabolite produced within the tumor microenvironment. Here, by applying single-cell reporter strategies in 3D collagen cocultures in vitro and progressing tumors in vivo, we show that adenosine weakens one-to-one pairing of activated effector CTLs with target cells, thereby dampening serial cytotoxic hit delivery and cumulative death induction. Adenosine also severely compromised CTL effector restimulation and expansion. Antagonization of adenosine A2a receptor (ADORA2a) signaling stabilized and prolonged CTL–target cell conjugation and accelerated lethal hit delivery by both individual contacts and CTL swarms. Because adenosine signaling is a near-constitutive confounding parameter in metabolically perturbed tumors, ADORA2a targeting represents an orthogonal adjuvant strategy to enhance immunotherapy efficacy.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1158/2326-6066.cir-22-0113
- https://aacrjournals.org/cancerimmunolres/article-pdf/10/12/1462/3226770/1462.pdf
- OA Status
- bronze
- Cited By
- 22
- References
- 59
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4297100972
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Raw OpenAlex JSON
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https://openalex.org/W4297100972Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1158/2326-6066.cir-22-0113Digital Object Identifier
- Title
-
Adenosine A2a Receptor Antagonism Restores Additive Cytotoxicity by Cytotoxic T Cells in Metabolically Perturbed TumorsWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2022Year of publication
- Publication date
-
2022-09-26Full publication date if available
- Authors
-
Jeroen Slaats, Esther Wagena, Daan Smits, Annemarie A. Berends, Ella Peters, Gert‐Jan Bakker, Merijn van Erp, Bettina Weigelin, Gosse J. Adema, Peter FriedlList of authors in order
- Landing page
-
https://doi.org/10.1158/2326-6066.cir-22-0113Publisher landing page
- PDF URL
-
https://aacrjournals.org/cancerimmunolres/article-pdf/10/12/1462/3226770/1462.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
bronzeOpen access status per OpenAlex
- OA URL
-
https://aacrjournals.org/cancerimmunolres/article-pdf/10/12/1462/3226770/1462.pdfDirect OA link when available
- Concepts
-
Cytotoxicity, Antagonism, Cytotoxic T cell, Cancer research, Adenosine receptor, Receptor, Pharmacology, Chemistry, Adenosine, Immunology, Biology, Biochemistry, In vitro, AgonistTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
22Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 4, 2024: 14, 2023: 4Per-year citation counts (last 5 years)
- References (count)
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59Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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